Breast cancer osteomimicry and its role in bone specific metastasis; an integrative,systematic review of preclinical evidence

Metastasis accounts for most of the deaths from breast cancer and the preference of invasive breast cancer metastasising to bone has been widely reported. However, the biological basis of breast cancer osteotropism is not fully understood. This paper provides, for the first time, an integrative, systematic review of evidence of molecular factors that have functional roles in the homing of metastatic breast cancer to the bone.Pubmed, Web of Science and EBSCOhost were searched using keywords and synonyms for molecular, metastasis, breast cancer and bone to identify articles published between January 2004 and August 2016. 4491 potentially relevant citations were retrieved. 63 articles met the inclusion criteria, which were primary studies reporting evidence of molecular factors that have functional roles in predisposing breast cancer bone metastasis in vivo. 12 of those 63 articles that additionally met quality criteria were included in the review. Extracted data were tabulated and key findings that indicated biological mechanisms involved in breast cancer metastasis to bone were synthesised.15 proteins expressed by breast cancer cells were identified as factors that mediate breast cancer bone metastasis: ICAM-1, cadherin-11, osteoactivin, bone sialoprotein, CCN3, IL-11, CCL2, CITED2, CXCR4, CTGF, OPN, CX₃CR1, TWIST1, adrenomedullin and Enpp1. Upregulation or overexpression of one or more of them by breast cancer cells resulted in increased breast cancer metastasis to bone in vivo, except for CCL2 where bone-metastatic cells showed a reduced expression of this factor. All factors identified, here expressed by breast cancer cells, are proteins that are normally expressed in the bone microenvironment and linked to physiologic bone functions. All have a functional role in one of more of the following: cell proliferation and differentiation, bone mineralization and remodelling, cell adhesion and/or chemokine signalling. Six of them (cadherin-11, ICAM-1, OPN, CX₃CR1, CCN3 and osteoactivin) have a reported function in cell adhesion and another eight (CCN3, osteoactivin, Enpp1, IL-11, CTGF, TWIST1, adrenomedullin and CITED2) are reported to be involved in cell proliferation and differentiation.This review collates and synthesises published evidence to increase our understanding of the biology of breast cancer osteomimicry in the development of bone metastasis. Findings of this review suggest that changes in expression of proteins in breast cancer cells that confer osteomimicry facilitate homing to bone to enable the development of bone metastasis.     

Expression of Na＋-dependent glucose transporter 1 and 2 in peritoneum of peritoneal dialysis patients

Objective To investigate the expression of Na＋-dependent glucose transporter (SGLT) in human peritoneal mesothelial cells (HPMCs) and vascular endothelial cells in peritoneal tissues of peritoneal dialysis (PD) patients at different dialysis vintages, and to study the influence of high glucose treatment on the expression of SGLT1 and SGLT2 in primary HPMCs. Methods According to the dialysis vintage, PD patients were divided into four groups: 0 year group, ＞0-2 years group, ＞2-4 years group and＞4 years group. HE and Masson staining were used to observe the morphologic changes of peritoneal tissues in PD patients. Immunohistochemical staining was used to detect the expression of SGLT1 and SGLT2 in peritoneal HPMCs and vascular endothelial cells. The primary HPMCs were extracted from the peritoneal dialysis fluid, and treated with high-glucose or high-mannitol for 0 h, 12 h, 24 h, 48 h, 72 h and 96 h. Western blotting was used to investigate the SGLT1 and SGLT 2 expression in HPMCs. The cell viability was detected by using cell counting kit (CCK-8). Results HE and Masson staining showed that the peritoneum of PD patients in 0 year group was smooth and continuous, with a flat layer of HPMCs. The number of HPMCs in＞0-2 years group decreased compared with that in 0 year group. The HPMCs size increased in＞2-4 years group, but the number decreased. The peritoneum of PD patients in＞4 years group was significantly thickened and fibrotic, and HPMCs almost disappeared. Immunohistochemical staining showed that the expression of SGLT1 and SGLT2 in HPMCs gradually decreased with the increase of dialysis vintage (P＜0.05). The wall of peritoneal blood vessel became thicken, but the expression of SGLT1 and SGLT2 was not statistically different among four groups (P＞0.05). SGLT1 in primary HPMCs could be up-regulated (0 h, 12 h and 24 h), and then down-regulated (24 h, 48 h, 72 h, 96 h) with the treatment of 60 mmol/L glucose (P=0.029); but there was no significant difference of SGLT2. Conclusion High glucose and the increase of dialysis vintage can reduce the number and the viability of HPMCs, and decrease the expression of SGLT1 and SGLT2, but there was no significant influence on SGLT1 and SGLT2 in peritoneal vascular endothelial cells.     

肠道菌群在肾脏疾病及治疗中的研究进展

肾脏疾病会影响肠道菌群的结构和丰度,而肠道菌群的紊乱也会增加尿毒症毒素的产生,加速肾脏疾病的进程。本文阐述了肠道菌群的构成和作用,探讨了肠道菌群与慢性肾脏病（chronic kidney disease,CKD）、终末期肾病（end-stage renal disease,ESRD）、腹膜透析、血液透析和肾移植的关系,并列举了通过调节肠道菌群治疗肾脏疾病的各类方法,包括饮食疗法、益生菌、益生元、合生元、碳吸附剂和粪菌移植。     

Reduction of correlation dimension in human respiration by inhaling a mixture gas of 5% carbon dioxide and 95% oxygen

In order to investigate the effect of the respiratory control system on deterministic behavior in respiration, we used nonlinear analysis in subjects breathing a mixture gas of 5% carbon dioxide (CO₂) and 95% oxygen (O₂) (CO₂–mixed gas). The respiratory movements during breathing air or CO₂–mixed gas in eight healthy volunteers were measured. We estimated the values of the correlation dimension (D2) in respiratory movement using Grassberger–Procaccia algorithm. The respiratory movements during inhaling either air or CO₂–mixed gas showed a nonlinear behavior using surrogate data method. The values of D2 in respiratory movement during inhaling CO₂–mixed gas (1.77 ± 0.17) were significantly smaller than those during inhaling air (2.52 ± 0.60) (P < 0.05). This might be related to a prompt change in the nonlinear signal from the central respiratory chemical system.     

Genetic spectrum of renal disease for 1001 Chinese children based on a multicenter registration system

To explore the approaches and diagnostic yield of genetic testing for renal disease in children, we describe the genotype and phenotype of the national cohort of children with renal disease from 13 different regions of China recruited from 2014 to 2018 by building up the multicenter registration system (Chinese Children Genetic Kidney Disease Database, CCGKDD). Genetic diagnosis was confirmed in 42.1% of our cohort of 1001 pediatric patients with clinical suspicion of a genetic renal disease. Of the 106 distinct monogenetic disorders detected, 15 accounted for 60.7% of genetic diagnoses. The diagnostic yield was 29.1% in steroid resistant nephritic syndrome (SRNS), 61.4% in cystic renal disease, 17.0% in congenital anomalies of the kidney and urinary tract (CAKUT), 62.3% in renal tubular disease/renal calcinosis, and 23.9% for chronic kidney disease (CKD) 3 to 5 stage with unknown origin. Genetic approaches of target gene sequence (TGS), singleton whole-exome sequencing (WES) and trio-WES were performed with diagnostic rates of 44.8%, 36.2%, and 42.6%, respectively. The early use of trio-WES could improve the diagnostic rate especially in renal tubular disease and calcinosis. We report the genetic spectrum of Chinese children with renal disease. Establishment of the CCGKDD will improve the genetic work on renal disease.     

Pro-inflammatory cytokines as potential predictors for intradialytic hypotension

BackgroundIntradialytic hypotension (IDH) is a common complication in maintaining hemodialysis (MHD) patients. Immune activation might be part of the mechanisms. However, the association between pro-inflammatory cytokines and blood pressure (BP) has not been deeply explored. So we aim to evaluate the potential role of pro-inflammatory cytokines in IDH.MethodsMHD patients starting hemodialysis before January 2016 were enrolled in our retrospective study. Patients'' characteristics, laboratory results, and intradialytic BP were collected. IDH was defined as nadir systolic BP ≤ 90 mmHg during hemodialysis. The definition of IDH group was that those who suffered from more than one hypotensive event during one month after the enrollment (10% of dialysis treatments). Spearman correlation analysis and logistic regression were employed to explore the relationship between pro-inflammatory cytokines and IDH.ResultsAmong 390 patients, 72 were identified with IDH (18.5%). High levels of serum tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were observed in the IDH group (p < 0.001). Both TNF-α and IL-1β positively correlated with predialysis BP (p < 0.01). Receiver operating characteristic curve (ROC) analysis was used to evaluate the diagnostic accuracy of serum IL-1β and TNF-α for IDH. The area under the curve of IL-1β was 0.772 (95% CI: 0.708-0.836, p < 0.01), and that of TNF-α was 0.701 (95% CI: 0.620-0.781, p < 0.01). After adjusting for patients'' characteristics, biochemical parameters, comorbid conditions, predialysis BP, and medications, elevated TNF-α and IL-1β were still risk factors for IDH.ConclusionPro-inflammatory cytokines (TNF-α and IL-1β) could be potential predictors for IDH.     

Effects of efonidipine hydrochloride (NZ-105), a new calcium antagonist,against acute renal failure in rats

• 1.1. We investigated the effect of efonidipine hydrochloride (NZ-105) against acute renal failure (ARF) in male Wistar rats. ARF was produced by ischemia or glycerol.
• 2.2. Ischemia-induced ARF was produced by right nephrectomy and clamping of the left renal artery for 60 min, followed by reperfusion. NZ-105 (20 mg/kg) was orally administered twice a day for 3 days before ARF. The plasma creatinine and urea nitrogen concentrations were markedly elevated in the ischemia ARF group on the 1st day, but the elevation was significantly suppressed by NZ-105 treatment.
• 3.3. Glycerol-induced ARF was produced by intramuscular injection of 50% (v/v) glycerol (10 ml/kg) in rats which were restricted to drinking water for 24 hr. NZ-105 (20 mg/kg) was orally administered twice a day for 3 days before ARF. NZ-105 significantly attenuated the severe impairment of creatinine and urea nitrogen clearances and the elevated fractional sodium excretion (FE_Na) caused by ARF.
• 4.4. In the kidney homogenate, NZ-105 (10⁻⁶−10⁻⁴ M) inhibited lipid peroxidation induced by ascorbic acid and Fe or by NADPH and the inhibitory effect of NZ-105 was stronger than α-tocopherol, an antioxidant agent. NZ-105 (10⁻⁵−10⁻³ M) showed radical scavenging action against diphenyl-p-picrylhydrazyl and galvinoxyl induced radicals.
• 5.5. These findings suggest that NZ-105 prevents the renal damage caused by the two kinds of ARF. Moreover, the inhibitory effects of NZ-105 against lipid peroxidation and radical formation may be one of the mechanisms involved in the prevention of ARF.